tbuckley/cabot-search huggingface dataset:
P1198: A POPULATION-BASED STUDY REVEALS THE UNIQUE CLINICAL CHARACTERISTICS AND LONG-TERM SURVIVAL OF PATIENTS WITH GRAY ZONE LYMPHOMA
Authors: Xin Wang, Ailin Zhao, Ting Niu
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Gray zone lymphoma (GZL) is a rare disease entity with pathological features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (HL). Given its rarity, a relative paucity of clinical data exists describing GZL, constraining our ability to better understand the clinical features and outcomes of GZL. Aims: In this study, we analyzed detailed clinical features, outcomes, and prognostic factors of patients with GZL. Methods: Chemotherapy-treated patients with GZL diagnosed between 2000 and 2018 were selected. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Cox and Fine-Gray regression models were used to evaluate overall and GZL-specific survival, respectively. Results: A total of 211 patients were selected. Most patients were aged 55 years or older (51.7%). The lymph node was the most common primary site (85.3%). Patients with nodal primary sites presented more often with B symptoms (P = 0.041) and advanced-stage disease (P < 0.001). The 5-year overall survival (OS) rates and lymphoma-specific death rates of treated GZL patients were 75.1% (95% CI: 69.0%-81.2%) and 20.8% (95% CI: 15.1%-26.5%), respectively. Patients receiving combined radiotherapy had improved OS (P = 0.011) and lymphoma-specific survival (LSS, P = 0.031). Other independent prognostic factors included age, ethnicity and race. Patients who received combined radiotherapy, without B symptoms, Hispanic, and younger than 55 years generally had higher 3-year conditional survival (CS) rates. Summary/Conclusion: This study set an age cutoff of 55 years, which provided an excellent estimate for the prognosis of GZL. It identified that B symptoms, ethnicity and race were the prognostic factors for OS, LSS and CS. It is found that combined radiotherapy improved OS and LSS, and treated GZL patients may achieve long-term survival. Keywords: Lymphoma, Clinical outcome, Clinical data, Survival prediction
YAP/TAZ: Molecular pathway and disease therapy
Authors: Yuzi Wei, Victoria Lee Zhi Hui, Yilin Chen, Ruiying Han, Xianglong Han, Yongwen Guo
Journal: MedComm (2023)

The Yes-associated protein and its transcriptional coactivator with PDZ-binding motif (YAP/TAZ) are two homologous transcriptional coactivators that lie at the center of a key regulatory network of Hippo, Wnt, GPCR, estrogen, mechanical, and metabolism signaling. YAP/TAZ influences the expressions of downstream genes and proteins as well as enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, and the transdifferentiation of fibroblasts into myofibroblasts. YAP/TAZ can also be regulated through epigenetic regulation and posttranslational modifications. Consequently, the regulatory function of these mechanisms implicates YAP/TAZ in the pathogenesis of metabolism-related diseases, atherosclerosis, fibrosis, and the delicate equilibrium between cancer progression and organ regeneration. As such, there arises a pressing need for thorough investigation of YAP/TAZ in clinical settings. In this paper, we aim to elucidate the signaling pathways that regulate YAP/TAZ and explore the mechanisms of YAP/TAZ-induce diseases and their potential therapeutic interventions. Furthermore, we summarize the current clinical studies investigating treatments targeting YAP/TAZ. We also address the limitations of existing research on YAP/TAZ and propose future directions for research. In conclusion, this review aims to provide fresh insights into the signaling mediated by YAP/TAZ and identify potential therapeutic targets to present innovative solutions to overcome the challenges associated with YAP/TAZ.
P1523: IMMUNOGENICITY OF THE 13-VALENT PNEUMOCOCCAL CONJUGATED VACCINE FOLLOWED BY THE 23-VALENT POLYSACCHARIDE VACCINE IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Sabine Haggenburg, Hannah Garcia Garrido, Iris Kant, Hanneke van der Straaten, Fransien De Boer, Sabina Kersting, Djamila Issa, Doreen Te Raa, Hein Visser, Arnon Kater, Abraham Goorhuis, Koen De Heer
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Patients with Chronic Lymphocytic Leukemia (CLL) have a 36-fold increased risk of invasive pneumococcal disease (IPD) compared to healthy adults. Therefore, most guidelines recommend vaccination with Prevenar13®, a 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by Pneumovax23®, a 23-valent polysaccharide vaccine (PPSV23). While CLL as well as immunosuppressive treatment have been identified as major determinants of vaccination-induced immunogenicity, knowledge about the immunogenicity of this sequential pneumococcal vaccination schedule in CLL patients is lacking. Aims: To assess the immunogenicity of the sequential vaccination schedule of PCV13 followed by PPSV23 in treatment naive and treated CLL patients. Methods: We quantified pneumococcal immunoglobulin G (IgG) antibody concentrations against 5 pneumococcal serotypes shared across both vaccines (6B, 9V, 14, 19F, 23F), and against 4 serotypes unique to PPSV23 (8, 15B, 20, 33F), prior to and 4-8 weeks after vaccination using a validated multiplex immunoassay, Luminex®. The primary outcome was the serologic response rate, defined as a ≥4-fold increase in ≥70% of the serotype-specific anti-pneumococcal IgG antibodies. Secondary outcome was serologic protection, defined as an antibody concentration of ≥1.3 mcg/ml for ≥70% of all measured serotypes. Results: In this retrospective cohort study, we included 143 CLL patients, either treated (n=38) or naive to treatment (n=105), who previously completed the vaccination and measurement schedule. Median time since CLL diagnosis was 3.6 years. While serotype-specific antibody concentrations increased significantly after vaccination, the overall serologic response rate of 10.5% was low, and significantly influenced by treatment status and prior lymphocyte count. The serotype-specific pneumococcal IgG antibody concentrations after vaccination were all significantly lower in treated than in previously untreated patients. The serologic protection rate was obtained in 13% of untreated and 3% of treated CLL patients. Summary/Conclusion: Despite this poor immunogenicity in CLL patients, vaccination is still recommended, because the high incidence of IPD in this population probably offsets the lower serologic response, but research should focus on vaccine regimens with a higher immunogenic potential, such as multi-dose schedules with higher-valent T cell dependent conjugate vaccines. Keywords: Infection, Vaccination, Chronic lymphocytic leukemia, Immunodeficiency
Cancer stem cells in brain tumors: From origin to clinical implications
Authors: Shuyun Lin, Kaishu Li, Ling Qi
Journal: MedComm (2023)

Malignant brain tumors are highly heterogeneous tumors with a poor prognosis and a high morbidity and mortality rate in both children and adults. The cancer stem cell (CSC, also named tumor-initiating cell) model states that tumor growth is driven by a subset of CSCs. This model explains some of the clinical observations of brain tumors, including the almost unavoidable tumor recurrence after initial successful chemotherapy and/or radiotherapy and treatment resistance. Over the past two decades, strategies for the identification and characterization of brain CSCs have improved significantly, supporting the design of new diagnostic and therapeutic strategies for brain tumors. Relevant studies have unveiled novel characteristics of CSCs in the brain, including their heterogeneity and distinctive immunobiology, which have provided opportunities for new research directions and potential therapeutic approaches. In this review, we summarize the current knowledge of CSCs markers and stemness regulators in brain tumors. We also comprehensively describe the influence of the CSCs niche and tumor microenvironment on brain tumor stemness, including interactions between CSCs and the immune system, and discuss the potential application of CSCs in brain-based therapies for the treatment of brain tumors.
P764: DIFFERENTAL ERYTHROPOIESIS IN BONE MARROW OF PNH PATIENTS WERE REVEALED BY SINGLE-CELL SEQUENCING
Authors: Hui Liu, Wei Wang, Lijie Zeng, Zhaoyun Liu, Liyan LI, Zonghong Shao, Rong Fu
Journal: HemaSphere (2023)

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonogenic disease of hematopoietic stem cells, which is characterized by intravascular hemolysis. In previous study, we have found increased erythrocytosis in bone marrow PNH clone by single cell sequencing. While the changes of differentiation in erythroid remains unclear. Aims: We aimed to explore the differentiation in erythroid cells about CD59+/- cells in PNH. Methods: Bone marrow mononuclear cells were acquired from 3 PNH patients and 4 healthy controls. CD59+ and CD59- cells were sorted by flow cytometry in PNH patients. Then we performed deep single-cell RNA sequencing for all cell lines of hematopoietic cells. We deeply analyzed the differentiation of increased erythroid in bone marrow PNH clone. Results: Six clusters of erythropoietic cells in PNH patients and normal controls were identified in our study, and marker genes of different clusters were identified by single cell sequencing. We found the cluster 4 and 5 represented erythroid progenitors (EP), which highly expressed FAM178B in cluster 4 and CD34 in cluster 5. Compared with normal controls, cluster 5 decreased obviously in CD59- clone of PNH patients, while there was no changes of cluster 4 in controls and PNH patients. Interestingly, we found that CD63 was highly expressed in cluster 5, indicating it maybe associated with immune reaction. Other 4 clusters represented erythroid precursors, which highly expressed GYPA gene. Cluster 0 was characterized by active cell cycling, with significant enrichment of nuclear division; Cluster 1 was characterized by globin gene expression; Cluster 3 showed highly expressed genes associated with neutrophil and monocyte signatures, with high expression of CD74, LYZ, S100A8 and S100A9. Meanwhile, we found that cluster 1 increased obviously in CD59+ and CD59- cells of PNH patients, and cluster 3 decreased in CD59+ cell of PNH patients. Futhermore, we screened DEGs in normal controls, CD59- and CD59+ cells in PNH patietns. There were some upregulated genes in CD59+ clone, such as MK167, HBG1/2, IFIT1B, LYZ, et al; and some downregulated genes, such as IGHA1, TMSB4X, RPS29, CCL5, IL32, et al. Summary/Conclusion: We observed the changes of bone marrow erythropoiesis in PNH patients for the first time, and identified six clusters by single cell sequencing, which were abnormal in CD59- clone.Keywords: Erythroid lineage, RNA-seq, Paroxysmal nocturnal hemoglobinuria (PNH)
P618: LONG-TERM SAFETY WITH ≥12 MONTHS OF PIRTOBRUTINIB IN RELAPSED/REFRACTORY (R/R) B-CELL MALIGNANCIES
Authors: Wojciech Jurczak, Catherine C. Coombs, Nirav N. Shah, Jennifer Woyach, Chan Y. Cheah, Krish Patel, Kami Maddocks, Yucai Wang, Catherine E. Muehlenbein, Chunxiao Wang, Sarang Abhyankar, Donald E. Tsai, Toby A. Eyre
Journal: HemaSphere (2023)

Background: While Bruton tyrosine kinase inhibitors (BTKi) can induce sustained remissions, ongoing response requires continuous treatment and thus long-term safety/tolerability is critical for adherence, maintaining dose intensity, and delivering maximum efficacy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi approved by the FDA in January 2023 for R/R mantle cell lymphoma after 2 prior lines of therapy including a BTKi. Pirtobrutinib has demonstrated promising efficacy with low discontinuation and dose reduction rates in patients (pts) with multiple subtypes of R/R B-cell malignancies. However, the long-term safety and tolerability of pirtobrutinib has not yet been reported. Aims: Here we report the clinical safety in pts with long-term (≥12 months) pirtobrutinib treatment from the phase 1/2 BRUIN trial. Methods: Pts with R/R B-cell malignancies who received ≥12 months of pirtobrutinib were included. Median time to onset, dose reduction, discontinuation, and cumulative incidence rates were determined for treatment emergent adverse event (TEAE) that occurred in ≥20% of pts and select AE of interest associated with BTKi. Results: As of 29 July 2022, 773 pts were enrolled, and 326 (42%) pts received treatment for ≥12 months. Among these 326 pts, median time on treatment was 19 months (IQR: 16,25), with 231 (71%) remaining on pirtobrutinib. The most common TEAE (all grade, regardless of attribution) in this long-term 326 pt cohort were fatigue (32%), diarrhea (31%), Covid-19 (29%), contusion (26%), cough (25%), and back pain (21%). TEAE leading to dose reduction or discontinuation occurred in 23 (7%) and 11 (3%) pts, respectively. Four (1%) pts discontinued due to a treatment-related AE, and 1 pt had a fatal treatment-related AE (Covid-19 pneumonia). Select AE of interest for the long-term pts are shown in the Table. Comprehensive safety analyses describing the frequency of TEAE over time will be presented. Summary/Conclusion: Prolonged pirtobrutinib therapy continues to demonstrate a safety profile amenable to long-term administration at the recommended dose without evidence of new or worsening toxicity signals. The safety and tolerability observed in pts on therapy for ≥12 months was similar to previously published safety analyses on all pts enrolled regardless of follow-up.© 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. Keywords: relapsed/refractory, Chronic lymphocytic leukemia, Bruton’s tyrosine kinase inhibitor (BTKi)
S289: PPP1R1B BINDS IRON REGULATORY PROTEINS AND MODULATES IRON CELLULAR CONTENT
Authors: Laura Calvo López, Gonzalo Hernández, Ferran Celma Nos, Mayka Sanchez
Journal: HemaSphere (2023)

Background: The IRP/IRE post-transcriptional regulatory system controls iron cellular level by modifying the expression of several proteins related to iron acquisition, mobilization and storage. This regulation is achieved by the binding of the IRP1 and IRP2 proteins to the IRE-containing UTRs in iron-deficient conditions. Previously we described the complete IRP RNP regulon system in mice (Sanchez et al 2011 Blood) identifying more than 260 mRNAs that immunoprecipitate with IRP1 and/or IRP2. Aims: Protein phosphatase 1 regulatory inhibitor subunit 1b, Ppp1r1b (encoding DARPP-32 protein) was detected as an mRNA that binds IRP1 and IRP2 in duodenum and brain. Here we focus on the characterization of the IRP/IRE regulation of the PPP1R1B gene and its role in iron metabolism. Methods: By means of EMSAs we have studied the capability of the human and mouse PPP1R1B/Ppp1r1b IRE structures to bind both IRP1 and IRP2 in vitro. Additionally, immunoblots were done to study the modulation of DARPP-32 protein by iron. Atomic absorption spectrometry was used to measure the cellular iron content in HeLa cells overexpressing the WT and phosphomutants forms of DARPP-32. Results: A 5’IRE was bioinformatically predicted in mouse Ppp1r1b mRNA. Our results indicate that the mouse Ppp1r1b 5’IRE is able to bind recombinant IRP1 in direct and competitive EMSAs in vitro. In addition, using 2 human cell lines (duodenal and neuronal) we observed iron modulation of human DARPP-32 protein in response to iron, consistently with an IRP/IRE regulation by a 5’IRE. Interestingly, overexpression of human DARPP-32 in HeLa cells caused a marked reduction in the cellular iron content, similarly as detected by Ferroportin overexpression (used as control). Using the mouse Ppp1r1b gene for overexpression in HeLa cells, a similar trend of iron depletion was found; although it did not reach statistical significance (more experiments are ongoing). We are currently investigating the molecular mechanism involved in the modulation of cellular iron content by PPP1R1B. Summary/Conclusion: The discovery of new mRNAs regulated by the IRPs will help in a better understanding of the IRP/IRE regulatory system and to unveil new functions of genes not previously linked to iron homeostasis. This study provides evidence that mouse Ppp1r1b mRNA contains a functional 5’IRE and binds IRPs in vitro. Cell culture experiments demonstrate that human DARPP-32 protein levels are regulated by iron cellular status as it would be expected for genes regulated by IRPs and we discover that DARPP-32 modulates cellular iron content. Keywords: Gene regulation, Iron, Iron metabolism
TMEM106B aggregation in neurodegenerative diseases: linking genetics to function
Authors: Hai-Shan Jiao, Peng Yuan, Jin-Tai Yu
Journal: Molecular Neurodegeneration (2023)

Abstract Background Mutations of the gene TMEM106B are risk factors for diverse neurodegenerative diseases. Previous understanding of the underlying mechanism focused on the impairment of lysosome biogenesis caused by TMEM106B loss-of-function. However, mutations in TMEM106B increase its expression level, thus the molecular process linking these mutations to the apparent disruption in TMEM106B function remains mysterious. Main body Recent new studies reported that TMEM106B proteins form intracellular amyloid filaments which universally exist in various neurodegenerative diseases, sometimes being the dominant form of protein aggregation. In light of these new findings, in this review we systematically examined previous efforts in understanding the function of TMEM106B in physiological and pathological conditions. We propose that TMEM106B aggregations could recruit normal TMEM106B proteins and interfere with their function. Conclusions TMEM106B mutations could lead to lysosome dysfunction by promoting the aggregation of TMEM106B and reducing these aggregations may restore lysosomal function, providing a potential therapeutic target for various neurodegenerative diseases.
PB2353: PROGNOSTIC VALUE OF TIME FROM SYMPTOMS BEGIN TO START TREATMENT IN DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Sunil Lakhwani Lakhwani, Ignacio Artiles Santana, Belén Pérez-Pinilla, Alvaro Bienert Garcia, Minerva Montalvo Saavedra, Marta Díaz-Lopez, Carolina De Bonis-Braun, María José Rodríguez Salazar, Patricia Machado-Machado, Miguel Teodoro Hernandez Garcia, Jose Maria Raya
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Diffuse large B-cell lymphoma (DLBCL) constitutes approximately 30% of adult non-Hodgkin lymphomas in developed countries, and even a higher percentage in developing countries. It is the paradigm of aggressive lymphomas and with standard treatment 5-year overall survival ranges from 60 to 70%. As in other aggressive malignancies delay in diagnosis and consequently delay in starting effective treatment could influence in prognosis, but it has not been studied properly. Aims: Evaluate the prognosis value of delay in diagnosis and starting treatment in patients with DLBCL. Methods: We reviewed medical records of 52 consecutive patients (male 50%, mean age 66 years, range 18-91) with a diagnosis of DLBCL treated in our institution between 2010 and 2015. We defined to times: a) time from any symptoms related to lymphoma begin until starting treatment and b) time from first visit to a hematologist or oncologist until starting treatment. Both progression free survival (PFS) and overall survival (OS) began to be counted from the start of treatment. Results: Most of the 52 patients analyzed were stage IV (53,8%), had elevated LDH (61,5%) and had an IPI score of intermediate-high or high risk (55,8%). Of note 38 patients were managed as inpatient and 14 patients as outpatients. Complete response was achieved with first line treatment in 33 patients (63,5%) of which 9 patients (17,3% of total) suffered a relapse. Median time from symptoms started to begin treatment was 108 days (range 31 to 409 days) with mean time of 130 days. Patients with more than 130 days from symptoms to treatment had worse OS than patients with less than 130 days (p=0,018; Figure 1). Although PFS curves between patients with more or less than 130 days separate from each other, differences were only near statistically significance (p=0,11). Mean time from first hematologist or oncologist visit to treatment was 10 days (range 0 to 107 days) with a mean time of 19 days and this time was not associated with differences in PFS or OS. Univariate analysis was statistically significant for IPI, red cell distribution width and outpatient vs inpatient in addition to time from symptoms to treatment. In Cox regression model for multivariate analysis for OS including these factors, only time from symptoms to treatment more or less than 130 days were statistically significant. Summary/Conclusion: Time from symptoms start until we administrate treatment is an independent prognosis factor for OS in DLBCL. Efforts for earlier diagnosis should be made to avoid worsening prognosis.Keywords: Prognosis, DLBCL
Protein regulator of cytokinesis 1: a potential oncogenic driver
Authors: Sijing Li, Omar Motiño, Flavia Lambertucci, Isabelle Martins, Li Sun, Guido Kroemer
Journal: Molecular Cancer (2023)

Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis. Growing evidence suggests the association of PRC1 with multiple cancers. Here, we unveil that, in 28 cancer types, PRC1 is higher expressed in tumor tissues than in non-malignant tissues. Overexpression of PRC1 indicates unfavorable prognostic value, especially in ACC, LGG, KIRP, LICH, LUAD, MESO, PAAD, SARC and UCEC, while methylation of the PRC1 gene at sites associated with its inactivation has a favorable prognostic value in ACC, KIRP, LUAD, MESO, KIRP and LGG. Differentially expressed genes (DEGs) associated with high (> median) PRC1 expression contribute to key signaling pathways related with cell cycle, DNA damage and repair, EMT, cell migration, invasion and cell proliferation in most cancer types. More specifically, the DEGs involved in RAS/RAF/MAPK, PI3K/AKT, WNT, NOTCH, TGF-β, integrin, EMT process, focal adhesion, RHO GTPase-related pathway or microtubule cytoskeleton regulation are upregulated when PRC1 expression is above median, as confirmed for most cancers. Most importantly, high expression of PRC1 appears to be associated with an overabundance of poor-prognosis TH2 cells. Furthermore, positive correlations of PRC1 and some immune checkpoint genes (CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, TIGIT, and CD86) were observed in several cancers, especially BLCA, BRCA, KIRC, LUAD, LIHC, PRAD and THCA. These findings plead in favor of further studies validating the diagnostic and prognostic impact of PRC1 as well as the elaboration of pharmacological strategies for targeting PRC1.